CN115427422A - Compound comprising beta-nicotinamide mononucleotide or pharmacologically acceptable salt thereof, method for evaluating quality thereof, and method for determining enzymatic reactivity - Google Patents
Compound comprising beta-nicotinamide mononucleotide or pharmacologically acceptable salt thereof, method for evaluating quality thereof, and method for determining enzymatic reactivity Download PDFInfo
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- CN115427422A CN115427422A CN202180024394.2A CN202180024394A CN115427422A CN 115427422 A CN115427422 A CN 115427422A CN 202180024394 A CN202180024394 A CN 202180024394A CN 115427422 A CN115427422 A CN 115427422A
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- 230000009257 reactivity Effects 0.000 title claims abstract description 77
- 150000001875 compounds Chemical class 0.000 title claims abstract description 66
- 150000003839 salts Chemical class 0.000 title claims abstract description 39
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- 238000000034 method Methods 0.000 title claims description 59
- 230000002255 enzymatic effect Effects 0.000 title claims description 35
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- 108700023483 L-lactate dehydrogenases Proteins 0.000 claims abstract description 81
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 59
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- 210000002027 skeletal muscle Anatomy 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 4
- BAWFJGJZGIEFAR-DQQFMEOOSA-N [[(2r,3s,4r,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)O[P@@](O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-DQQFMEOOSA-N 0.000 claims 1
- 125000003275 alpha amino acid group Chemical group 0.000 claims 1
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- 239000000047 product Substances 0.000 description 20
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- -1 inorganic acid salt Chemical class 0.000 description 9
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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Abstract
The present invention is a compound containing beta-nicotinamide mononucleotide or a pharmacologically acceptable salt thereof, having a purity of 95% or more as measured by HPLC and a reactivity to lactate dehydrogenase of 30 units or more.
Description
Technical Field
The present invention relates to a compound containing β -nicotinamide mononucleotide or a pharmacologically acceptable salt thereof, a method for evaluating the quality thereof, and a method for determining enzymatic reactivity.
Background
Beta-nicotinamide mononucleotide (hereinafter sometimes referred to as "beta-NMN") is a biosynthetic intermediate metabolite of the coenzyme NAD +. In recent years, it has been reported that β -NMN has an effect of improving insulin secretion ability in aged mice, and an effect of greatly improving insulin sensitivity and secretion in a mouse model in which type 2 diabetes is induced by high-fat diet and aging (for example, see patent document 1); participating in control of circadian rhythm (see, for example, patent document 2); has the effect of obviously enhancing the mitochondrial function of aged muscles and the like. In addition, it has been reported that administration of β -NMN is useful for ameliorating or preventing symptoms of various diseases associated with aging, such as obesity, an increase in blood lipid concentration, a decrease in insulin sensitivity, a decrease in memory, and deterioration of eye functions such as macular degeneration (see, for example, patent document 3). In addition, administration of β -NMN is expected to increase the amount of NAD + in a living body, activate longevity genes (sirtuins), suppress or delay the decline in body functions associated with aging of the living body, and have an anti-aging effect (see, for example, patent document 4).
On the other hand, it has been proposed to crystallize β -NMN to improve its purity or to improve its storage stability when it is applied to medicines, supplements, cosmetics, and the like (see, for example, patent documents 5 and 6).
Documents of the prior art
Patent document
Patent document 1: description of U.S. patent No. 7737158
Patent document 2: U.S. patent application publication No. 2011/123510
Patent document 3: international publication No. 2014/146044
Patent document 4: international publication No. 2017/200050
Patent document 5: japanese patent laid-open publication No. 2018-534265
Patent document 6: international publication No. 2018/047715
Disclosure of Invention
[ problems to be solved by the invention ]
The present inventors have found that beta-nicotinamide mononucleotide produced by itself and a commercially available beta-NMN product have High purity when measured by High Performance Liquid Chromatography (hereinafter, may be referred to as "HPLC") in the same manner, but the same effect cannot be obtained even when the dose is the same when administered to a living body, and the same effect can be obtained even when the purity is improved by crystallization. That is, since β -NMN has the same purity as measured by HPLC but different physiological activities, it is necessary to provide β -NMN having higher physiological activity.
The present invention addresses the above-described needs by solving the various problems described above in the prior art and achieving the following objects. That is, an object of the present invention is to provide a method for evaluating the quality of a compound containing β -nicotinamide mononucleotide or a pharmacologically acceptable salt thereof, which has high purity as measured by HPLC and exhibits high enzymatic reactivity, and a method for determining the enzymatic reactivity.
[ means for solving problems ]
The present inventors have made extensive studies to achieve the above-mentioned object, and as a result, have found that the physiological activities differ from each other due to the difference in enzymatic reactivity of β -NMN in these preparations, although the purity of the preparations measured by HPLC is the same, thereby completing the present invention.
The present invention has been made based on the above findings by the present inventors, and a method for solving the above problems is as follows. That is to say that the first and second electrodes,
<1 > a compound which is a compound comprising β -nicotinamide mononucleotide or a pharmacologically acceptable salt thereof, characterized in that: the purity by HPLC measurement is 95% or more, and the reactivity to lactate dehydrogenase is 30 units or more.
<2 > the compound according to <1 > which has a purity of 98% or more as measured by HPLC and a reactivity of 33 units or more with respect to lactate dehydrogenase.
< 3> the compound according to the above <1 > or <2 >, which is in a crystalline form.
< 4 > the compound according to any one of the above <1 > to < 3>, wherein the lactate dehydrogenase is a lactate dehydrogenase derived from skeletal muscle of a mammal.
< 5 > the compound according to < 4 >, wherein the lactate dehydrogenase has the amino acid sequence of SEQ ID NO. 1.
< 6 > the compound according to any one of said <1 > to < 5 >, which is substantially free of nicotinamide dinucleotide.
< 7 > a method for evaluating the quality of a compound comprising β -nicotinamide mononucleotide or a pharmacologically acceptable salt thereof, comprising:
the quality of the compound containing β -nicotinamide mononucleotide or a pharmacologically acceptable salt thereof is evaluated using as an index a purity of 95% or more as measured by HPLC and a reactivity to lactate dehydrogenase of 30 units or more.
< 8 > a method for determining enzymatic reactivity of a compound containing β -nicotinamide mononucleotide or a pharmacologically acceptable salt thereof, comprising:
the reactivity of the composition containing beta-nicotinamide mononucleotide or a pharmacologically acceptable salt thereof with respect to lactate dehydrogenase is determined using as an index a purity of 95% or more as measured by HPLC and a reactivity with respect to lactate dehydrogenase of 30 units or more.
[ Effect of the invention ]
The present invention can solve the above-described problems and achieve the above-described object, and can provide a method for evaluating the quality of a compound containing β -nicotinamide mononucleotide or a pharmacologically acceptable salt thereof, which has high purity as measured by HPLC and exhibits high enzymatic reactivity, and a method for determining enzymatic reactivity.
Drawings
FIG. 1 is a diagram showing the reaction between β -NMN and lactate dehydrogenase.
FIG. 2 is a graph showing the enzymatic reactivity of a β -NMN compound and a commercially available β -NMN product of an example of the present invention to lactate dehydrogenase (SEQ ID NO: 1) measured in test example 1.
FIG. 3A is a graph showing the enzymatic reactivity of a β -NMN compound and a commercially available β -NMN preparation of an example of the present invention to porcine-derived Lactate Dehydrogenase (LDH) 1 (SEQ ID NO: 4) as measured in test example 3.
FIG. 3B is a graph showing the enzymatic reactivity of a β -NMN compound and a commercially available β -NMN preparation of an example of the present invention to human-derived Lactate Dehydrogenase (LDH) 1 (SEQ ID NO: 2) as measured in test example 3.
FIG. 3C is a graph showing the enzymatic reactivity of a β -NMN compound and a commercially available β -NMN preparation of an example of the present invention to human-derived Lactate Dehydrogenase (LDH) 5 (SEQ ID NO: 3) measured in test example 3.
FIG. 4A is a graph showing the relative activity values of lactate dehydrogenase (SEQ ID NO: 1) measured in test example 4 for various concentrations of the β -NMN compound of one example of the present invention and a commercially available β -NMN preparation 1.
FIG. 4B is a graph showing the relative activity values of lactate dehydrogenase (SEQ ID NO: 1) measured in test example 4 for various concentrations of the β -NMN compound of one example of the present invention and a commercially available β -NMN preparation 2.
FIG. 4C is a graph showing the relative activity values of lactate dehydrogenase (SEQ ID NO: 1) measured in test example 4 for various concentrations of the β -NMN compound of one example of the present invention and commercially available β -NMN preparation 3.
FIG. 4D is a graph showing the relative activity values of human-derived Lactate Dehydrogenase (LDH) 1 (SEQ ID NO: 2) measured in test example 4 for various concentrations of the β -NMN compound of one example of the present invention and a commercially available β -NMN preparation 1.
FIG. 4E is a graph showing the relative activity values of human-derived Lactate Dehydrogenase (LDH) 1 (SEQ ID NO: 2) measured in test example 4 for various concentrations of β -NMN compound of one example of the present invention and commercial β -NMN preparation 2.
FIG. 4F is a graph showing the relative activity values of human-derived Lactate Dehydrogenase (LDH) 1 (SEQ ID NO: 2) measured in test example 4 for various concentrations of a β -NMN compound according to an example of the present invention and a commercially available β -NMN preparation 3.
Fig. 5A is a graph showing cytotoxicity rates (cell failure rates) obtained from AST activities inside and outside cells measured in test example 5 using β -NMN compounds according to an example of the present invention.
Fig. 5B is a graph showing cytotoxicity rates obtained from intracellular and extracellular AST activities measured in test example 5 using β -NMN preparation 3.
Fig. 6A is a graph showing the intracellular NAD content measured in test example 5 using β -NMN compound according to an example of the present invention.
FIG. 6B is a graph showing the intracellular NAD content measured in test example 5 using β -NMN preparation 3.
Detailed Description
(Compound (I))
The compound of the present invention contains β -nicotinamide mononucleotide or a pharmacologically acceptable salt thereof, and has a purity of 95% or more as measured by HPLC and a reactivity to lactate dehydrogenase of 30 units or more.
beta-Nicotinamide mononucleotide has 2 optical isomers of alpha and beta, and the structure of beta-Nicotinamide mononucleotide (CAS number: 1094-61-7) of the present invention is shown below.
[ solution 1]
The compound containing β -NMN or a pharmacologically acceptable salt thereof (hereinafter, sometimes referred to as "β -NMN compound") of the present invention can be produced by any method. For example, β -NMN artificially synthesized by a chemical synthesis method, an enzymatic method, a fermentation method, or the like can be purified and used as an active ingredient. In addition, since β -NMN is a component widely present in living bodies, β -NMN obtained by extraction and purification from natural materials such as animals, plants, and microorganisms can be used as an active ingredient. In addition, commercially available purified β -NMN may also be used.
As a chemical synthesis method for synthesizing β -NMN, β -NMN can be produced by, for example, reacting nicotinamide with L-ribotetraacetic acid ester to phosphorylate the obtained nicotinamide mononucleotide. In addition, as the enzymatic method, for example, β -NMN can be produced from nicotinamide and 5 '-phosphoribosyl-1' -pyrophosphate (hereinafter, sometimes referred to as "PRPP") by nicotinamide phosphoribosyltransferase (hereinafter, sometimes referred to as "NAMPT"), or β -NMN can be produced from nicotinamide riboside by nicotinamide riboside kinase. In addition, as a fermentation method, for example, β -NMN can be produced from nicotinamide by utilizing the metabolic system of a microorganism expressing NAMPT.
The beta-NMN may also be a pharmacologically acceptable salt. The pharmacologically acceptable salt of β -NMN may be an inorganic acid salt or an organic acid salt having a basic site such as an amine. Examples of the acid constituting such an acid salt include: acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, vinylsulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, galactaric, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. The pharmacologically acceptable salt of β -NMN may be an alkali metal salt or an organic salt having an acidic site such as a carboxylic acid. Examples of the base constituting such an acid salt include alkali metal salts and alkaline earth metal salts derived from bases such as sodium hydride, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, trimethylamine, triethylamine, ethylenediamine, lysine, arginine, ornithine, choline, N' -dibenzylethylenediamine, chloroprocaine, procaine, diethanolamine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) -aminomethane, and tetramethylammonium hydroxide.
The β -NMN compound of the present invention may be in a crystalline form or an amorphous form (amophorus), but in order to suppress contamination of impurities and to further improve stability as a compound, it is preferable to crystallize the β -NMN compound obtained by a crystallization step using an alcohol-containing solution such as a methanol solution or ethanol. The crystallization method of the β -NMN compound is not particularly limited, and a known method can be appropriately selected, and for example, the crystallization can be performed according to the method described in japanese patent application laid-open No. 2018-534265 or international publication No. 2018/047715.
< purity by HPLC >
The purity of the β -NMN compound of the present invention is not particularly limited if the purity measured by HPLC (hereinafter, may be referred to as "HPLC purity") is 95% or more, and may be appropriately selected, but is preferably 98% or more.
The HPLC purity in the present invention means a ratio of a peak area derived from NMN to the total amount of each peak area detected by measuring a sample containing β -NMN by HPLC. Specifically, it can be obtained from the following equation.
-formula-
HPLC purity (%) = (peak area derived from β -NMN)/(total amount of measured peak areas) × 100
In the present invention, the HPLC analysis method for measuring HPLC purity is not particularly limited as long as the method and conditions for efficiently separating and measuring beta-NMN can be appropriately selected, and for example, hypercarb can be used TM (15 cm in length, 4.6mm in inner diameter, 3 μm in particle size, manufactured by Seimer Feishell scientific Co.) as a column, the measurement was carried out by the method described in Yoshino, et al, cell Metabolism,2011, vol.14, p.528-536 ", or the measurement was carried out by the method described in" Vitamin Amin journal, 1990, volume 64, no. 1, pages 19 to 25 ", using a TSK-GEL ODS column (15 cm in length, 4.6mm in inner diameter, 5 μm in particle size, manufactured by Tosoh Corp.). In the present invention, the measurement was performed by the following method.
HPLC machine used HPLC System development (Shimadzu corporation).
A β -NMN sample was dissolved in distilled water to 2mM to prepare a sample solution.
mu.L of the sample solution was applied to a TSK-GEL ODS-80TS column (length: 15cm, inner diameter: 4.6mm, particle size: 5 μm, manufactured by Tosoh Co., ltd.).
The separation of the β -NMN component adsorbed by the column can be carried out by the following method.
The elution was carried out by adjusting the flow rate to 0.7 mL/min under a concentration gradient of 0 to 15% methanol using 50mM tris acetate (pH 7.5)/methanol, and the absorbance was measured at 260 nm.
< enzyme reactivity >
The reactivity of the β -NMN compound of the present invention to lactate dehydrogenase (hereinafter, sometimes referred to as "enzyme reactivity") is not particularly limited if it is 30 units or more, and may be appropriately selected, but is preferably 33 units or more.
The lactate dehydrogenase (hereinafter, sometimes referred to as "LDH") in the present invention is a dehydrogenase also referred to as L-lactate dehydrogenase (EC 1.1.1.27).
The lactate dehydrogenase is preferably a skeletal muscle-derived lactate dehydrogenase derived from mammals, and more preferably a skeletal muscle-derived Lactate Dehydrogenase (LDH) 5 (hereinafter, sometimes referred to as "R-LDH 5") having an amino acid sequence of SEQ ID NO:1 and containing a tetramer of subunits, but other lactate dehydrogenases derived from mammals, such as a pig-derived Lactate Dehydrogenase (LDH) 1, a human-derived Lactate Dehydrogenase (LDH) 5, and the like, may be used. LDH is a substance that catalyzes dehydrogenation reaction and converts to pyruvate, but β -NMN is converted to reduced β -NMN in this case (see fig. 1).
In the present invention, the enzymatic reactivity refers to a value measured by the following reagents and methods.
< R1 reagent >
80mM Tris hydrochloride (pH 8.5)
·19mMβ-NMN
( The purity of β -NMN in the test sample was assumed to be 100%. In addition, beta-NMN was pre-dissolved in 80mM sodium carbonate solution )
< R2 reagent >
100mM Tris hydrochloride (pH 8.5)
100mM L-lactic acid
< enzyme solution >
The enzyme solution was adjusted so that the final concentration of LDH in the reaction solution reached 245U/mL.
In the present invention, the activity unit (U) of LDH is an activity unit when NAD is used as a coenzyme, and an activity unit when measured by a human LDH assay method conforming to the IFCC standard is used.
< Activity measurement >
For measuring the enzyme activity, hitachi autoanalyzer model 7180 (manufactured by Hitachi high and New technology Co., ltd.) was used. The measurement parameters are as follows.
Determination of parameters-
Analytical method. Class A
Measurement of wavelength (auxiliary/main. 405nm/340 nm)
20-24 light measuring spot
18. Mu.L of sample solution (enzyme solution). Cndot.
120. Mu.L of R1 reagent
87. Mu.L of R2 reagent
Determination of the order-
mu.L of the enzyme solution was mixed with 120. Mu.L of the R1 reagent, and after incubation at 37 ℃ for 4.5 minutes (photometric points 1-16), 87. Mu.L of the R2 reagent was added to start the reaction (photometric point 17). The absorbance change (. DELTA.mAbs/min) per minute was calculated by subtracting the absorbance of water (blank) at the same photometric point from the absorbance of the measurement sample at 1 to 2 minutes (photometric point 20-24) after the start of the reaction. The activity unit (the unit of reactivity to lactate dehydrogenase R-LDH 5) is 1 unit, which is the value of the change in absorbance per minute of 0.1 mAbs.
The β -NMN compound of the present invention preferably contains substantially no nicotinamide dinucleotide (hereinafter, sometimes referred to as "NAD"). The reason for this is that: when NAD is contained, the reactivity to lactate dehydrogenase may not be accurately measured.
In the present invention, the substantial absence of nicotinamide dinucleotide means that NAD in the β -NMN compound is not detected in the HPLC analysis described above. In addition, an embodiment in which NAD is contained in a preparation or food and drink in which the β -NMN compound of the present invention is formulated is not excluded.
The beta-NMN compound of the present invention has not only high purity as measured by HPLC, but also high enzymatic reactivity with lactate dehydrogenase. Therefore, the β -NMN compound of the present invention has higher bioavailability than conventional β -NMN products (drug substances), and has high quality and higher physiological action as β -nicotinamide mononucleotide or a pharmacologically acceptable salt thereof and a product containing the same. Therefore, the compound is very effective not only as a medicine containing β -NMN as an active ingredient, but also as a raw material for foods and beverages (including but not limited to supplements) or feeds, or can be administered or ingested to achieve a further effect.
(method of evaluating quality of Compound)
The method for evaluating the quality of a compound of the present invention is a method for evaluating the quality of a compound containing β -nicotinamide mononucleotide or a pharmacologically acceptable salt thereof, which comprises at least an evaluation step and, if necessary, further comprises other steps such as a measurement step.
< evaluation step >
The evaluation steps in the method for evaluating the quality of a compound of the present invention are as follows: the quality of a compound containing beta-nicotinamide mononucleotide or a pharmacologically acceptable salt thereof is evaluated using as an index a purity of 95% or more as measured by HPLC and a reactivity to lactate dehydrogenase of 30 units or more.
The index of purity measured by HPLC is not particularly limited if it is 95% or more, and may be appropriately selected, but is preferably 98% or more.
The index of the reactivity to lactate dehydrogenase is not particularly limited if it is 30 units or more, and may be appropriately selected, but is preferably 33 units or more.
Evaluation-
In the evaluation step in the method for evaluating the quality of a compound of the present invention, when the purity of a compound containing β -nicotinamide mononucleotide or a pharmacologically acceptable salt thereof to be evaluated as measured by HPLC is 95% or more and the reactivity to lactate dehydrogenase is 30 units or more, the quality of the compound to be evaluated is evaluated as good. More specifically, when the purity by HPLC is 95% or more and the reactivity to lactate dehydrogenase is 30 units or more, the evaluation target is a compound containing β -nicotinamide mononucleotide or a pharmacologically acceptable salt thereof, which has high bioavailability.
The purity and the reactivity to lactate dehydrogenase as measured by HPLC may be measured when the method for evaluating the quality of the compound of the present invention is performed, or may be separately measured.
< other steps >
The other steps in the method for evaluating the quality of the compound of the present invention are not particularly limited as long as the effects of the present invention are not impaired, and may be appropriately selected, for example, a measurement step or the like may be mentioned.
-a determination step-
The measurement steps in the method for evaluating the quality of a compound of the present invention are as follows: the purity and the reactivity to lactate dehydrogenase of a compound to be evaluated, which contains β -nicotinamide mononucleotide or a pharmacologically acceptable salt thereof, are measured by HPLC.
The purity and the reactivity to lactate dehydrogenase as measured by HPLC can be measured in the same manner as described in the item < HPLC purity > and the item < enzyme reactivity > of (compound) described above.
(method of determining enzymatic reactivity of Compound)
The method for determining the enzymatic reactivity of a compound of the present invention is a method for determining the enzymatic reactivity of a compound containing β -nicotinamide mononucleotide or a pharmacologically acceptable salt thereof, which comprises at least a determination step and, if necessary, further steps.
< decision step >
The method for determining the enzymatic reactivity of a compound of the present invention comprises the following steps: the enzymatic reactivity of a compound containing beta-nicotinamide mononucleotide or a pharmacologically acceptable salt thereof is determined using as an index a purity of 95% or more as measured by HPLC and a reactivity to lactate dehydrogenase of 30 units or more.
The index of purity measured by HPLC is not particularly limited if it is 95% or more, and may be appropriately selected, but is preferably 98% or more.
The index of the reactivity to lactate dehydrogenase is not particularly limited if it is 30 units or more, and may be appropriately selected, but is preferably 33 units or more.
-determining-
In the method for determining the enzymatic reactivity of a compound of the present invention, when the purity of a compound containing β -nicotinamide mononucleotide or a pharmacologically acceptable salt thereof to be determined by HPLC measurement is 95% or more and the reactivity to lactate dehydrogenase is 30 units or more, the determination step determines that the enzymatic reactivity to be determined is high. More specifically, when the purity is 95% or more as measured by HPLC and the reactivity to lactate dehydrogenase is 30 units or more, it is determined that the subject to be evaluated is a compound containing β -nicotinamide mononucleotide or a pharmacologically acceptable salt thereof having high reactivity to lactate dehydrogenase.
The purity and the reactivity to lactate dehydrogenase in the HPLC measurement may be measured in the case of performing the method for determining the enzymatic reactivity of the compound of the present invention, or may be measured separately.
< other step >
The other steps in the method for determining the enzymatic reactivity of the compound of the present invention are not particularly limited as long as the effect of the present invention is not impaired, and may be appropriately selected, for example, a measurement step or the like may be mentioned.
-a determination step-
The determination step in the method for determining the enzymatic reactivity of a compound of the present invention is the following step: the purity and the reactivity to lactate dehydrogenase of a compound to be evaluated, which contains β -nicotinamide mononucleotide or a pharmacologically acceptable salt thereof, are measured by HPLC.
The purity and the reactivity to lactate dehydrogenase as measured by HPLC can be measured in the same manner as described in the item < HPLC purity > and the item < enzyme reactivity > of (compound) described above.
According to the method for evaluating a compound and the method for determining enzymatic reactivity of a compound of the present invention, bioavailability that cannot be evaluated only by HPLC purity of β -nicotinamide mononucleotide or a pharmacologically acceptable salt thereof can be evaluated and determined, and thus a high-quality compound containing β -NMN or a pharmacologically acceptable salt thereof can be provided.
The present invention also includes a method for producing a high-quality compound containing β -NMN or a pharmacologically acceptable salt thereof, the method including a method for evaluating the compound or a method for determining the enzymatic reactivity of the compound.
Examples
The present invention will be described below by way of production examples and test examples, but the present invention is not limited to these production examples and test examples.
Production example 1
< enzyme treatment of beta-NMN >
About 100mg of beta-NMN reagent (amorphous, manufactured by Oriental Yeast Industrial Co., ltd.) was dissolved in 100mM phosphate buffer (pH 6.5), the pH was adjusted to 6.0 with 4N KOH, and 10,000U of R-LDH5 derived from skeletal muscle was added and reacted at 10 ℃ for 10 minutes. The reaction solution was subjected to ultrafiltration, and the filtrate was collected to recover β -NMN from which LDH was removed. The recovered solution containing beta-NMN was freeze-dried to obtain a beta-NMN sample in powder form.
< crystallization treatment >
Measuring water and ethanol in a test tube according to the volume ratio of 1:2, and dissolving the β -NMN sample therein to prepare a saturated aqueous solution of NMN. Thereafter, the aqueous solution was allowed to stand at 25 ℃ for 3 days to precipitate crystals. Subsequently, the solution containing crystals was centrifuged and the supernatant was removed. The crystals thus obtained were suspended in excess ethanol, and then centrifuged to remove the supernatant. Subsequently, crystals were obtained by heat-drying at 60 ℃ for 1 hour.
Production examples 2 to 4
The beta-NMN compound of the present invention was produced by using beta-NMN reagents of different production lots and performing the enzyme treatment and crystallization treatment in the same manner as in production example 1.
(test example 1)
In this test example, in addition to the β -NMN compound produced in production example 1, the following β -NMN products, which are commercially available and all of which were subjected to crystallization treatment, were used.
beta-NMN preparation 1 (fermentation preparation, manufactured by A Co., ltd.)
beta-NMN preparation 2 (chemical Synthesis product, manufactured by A Co., ltd.)
beta-NMN preparation 3 (product method: unknown, manufactured by B Co., ltd.)
< determination of HPLC purity >
The HPLC purity of the β -NMN compound (production example 1) and β -NMN products 1 to 3 of the present invention was measured by the following method. The results obtained are shown in table 1 below. The measurement results are the average values of 3 measurements.
[ HPLC purity measurement ]
HPLC machine used HPLC System development (Shimadzu corporation).
A β -NMN sample was dissolved in distilled water to 2mM to prepare a sample solution.
mu.L of the sample solution was applied to a TSK-GEL ODS-80TS column (length: 15cm, inner diameter: 4.6mm, particle size: 5 μm, manufactured by Tosoh Co., ltd.)
The separation of the beta-NMN component adsorbed by the column can be carried out by the following method.
The elution was carried out using 50mM Tris acetate (pH 7.5)/methanol, with a flow rate of 0.7 mL/min adjusted under a concentration gradient of 0 to 15% methanol, and the absorbance at 260nm was measured.
The HPLC purity was calculated from the total peak area of the obtained HPLC chart and the peak area of β -NMN by the following formula.
Formula-
HPLC purity (%) = (peak area derived from β -NMN)/(total amount of peak areas determined) × 100
< evaluation of enzyme reactivity >
The enzymatic reactivity with R-LDH5 (SEQ ID NO: 1) was evaluated for the beta-NMN compound of the present invention (preparation example 1) and beta-NMN preparations 1 to 3 by the following method. The obtained results are shown in table 1 and fig. 2. The measurement results are the average of 3 measurements.
[ evaluation of enzyme reactivity ]
-R1 reagent-
80mM Tris hydrochloride (pH 8.5)
·19mMβ-NMN
( The purity of β -NMN in the assay sample was assumed to be 100%. In addition, beta-NMN was pre-dissolved in 80mM sodium carbonate solution )
-R2 reagent-
100mM Tris hydrochloride (pH 8.5)
100mM L-lactic acid
Enzyme solution-
The enzyme solution was adjusted so that the final concentration of R-LDH5 in the reaction solution became 245U/mL.
Determination of the Activity
For the measurement of the enzyme activity, a 7180 Hitachi automatic analyzer (manufactured by Hitachi high and New technology Co., ltd.) was used. The measurement parameters are shown below.
Determining a parameter- -
Analytical method. Class A
Measurement of wavelength (auxiliary/main) 405nm/340nm
20-24 light measuring spot
18. Mu.L of sample solution (enzyme solution). Cndot.
120. Mu.L of R1 reagent
R2 reagent. Mu.L
-determination of the order- -
mu.L of the enzyme solution was mixed with 120. Mu.L of the R1 reagent, and after incubation at 37 ℃ for 4.5 minutes (photometric points 1-16), 87. Mu.L of the R2 reagent was added to start the reaction (photometric point 17). The absorbance change (. DELTA.mAbs/min) per minute was calculated by subtracting the absorbance of water (blank) at the same photometric point from the absorbance of the sample measured at 1 to 2 minutes (photometric point 20 to 24) after the start of the reaction, 5 minutes after the start of the reaction. The activity unit is 1 unit of 0.1mAbs absorbance change per minute.
[ Table 1]
From the results in table 1, the HPLC purities of the β -NMN compound of production example 1 and β -NMN products 1 to 3 were all 99% or more, but the enzyme reactivity of production example 1 was 39 units, and the enzyme reactivity of products 1 to 3 was as low as 23 to 26 units in terms of enzyme reactivity.
In addition, neither the β -NMN compound of preparation example 1 nor the β -NMN preparations 1 to 3 had a peak of NAD observed by HPLC, and NAD was not substantially contained.
(test example 2)
The β -NMN compounds produced in production examples 2 to 4 were measured for HPLC purity and enzyme reactivity by the same method as in test example 1. As a result, it was confirmed that the β -NMN compound of the present invention has high HPLC purity and high enzymatic reactivity even when raw materials having different production lots are used. These results are shown in table 2 below together with the test results of production example 1. The measurement results are the average of 3 measurements.
In addition, in none of the β -NMN compounds of production examples 2 to 4, no peak of NAD was observed in HPLC, and NAD was substantially not contained.
[ Table 2]
| Production example 1 | Production example 2 | Production example 3 | Production example 4 | |
| HPLC purity (%) | 99.9 | 99.98 | 99.8 | 99.7 |
| Enzyme reactivity (Unit) | 39 | 40 | 38 | 35 |
(test example 3)
< evaluation of enzymatic reactivity with LDHs derived from other animal species >
In order to confirm whether LDHs derived from other animal species and humans showed the same tendency, the β -NMN compound produced in production example 1 and β -NMN preparations 1 to 3 identical to those used in test example 1 were evaluated for their enzymatic reactivity to LDH ((a) porcine-derived LDH1, (B) human-derived LDH1, and (C) human-derived LDH 5).
The enzyme reactivity was evaluated in the same manner as in test example 1, except that the following enzyme solutions were used. The results obtained are shown in FIGS. 3A to C (FIG. 3A: porcine-derived LDH1, FIG. 3B: human-derived LDH1, FIG. 3C: human-derived LDH 5).
Enzyme solution-
(A) Pig-derived LDH1
The enzyme solution was adjusted so that the final concentration of LDH in the reaction solution reached 45U/mL.
(B) Human-derived LDH1
The enzyme solution was adjusted so that the final concentration of LDH in the reaction solution reached 45U/mL.
(C) Human-derived LDH5
The enzyme solution was adjusted so that the final concentration of LDH in the reaction solution reached 245U/mL.
From the results of test example 3, in the same manner as in test example 1, when the pig-derived LDH1, the human-derived LDH1 and the human-derived LDH5 were used, the enzyme reactivity of each of the products 1 to 3 to the β -NMN compound of production example 1 was low.
(test example 4)
< beta-NMN Compound concentration dependence of LDH Activity value >
In order to confirm the concentration dependency of the LDH activity value on the β -NMN compound, the β -NMN compound produced in production example 1 and the same β -NMN preparations 1 to 3 as used in test example 1 were used, and the enzyme activity of LDH was measured after changing the β -NMN concentration in the R1 reagent.
For measuring the enzymatic activity of LDH, the measurement was carried out in the same manner as in [ evaluation of enzymatic reactivity ] of test example 1 except that the following R1 reagent and enzyme solution were used, and the absorbance change per minute (. DELTA.mAbs/min) was calculated. The relative activity (%) of each NMN at each concentration is shown in FIGS. 4A to F (FIGS. 4A to C: R-LDH5, FIGS. 4D to F: human-derived LDH 1), assuming that the LDH activity value when 200mM of the β -NMN compound of production example 1 was used was 100%. The measurement results are the average of 3 measurements.
-R1 reagent-
80mM Tris hydrochloride (pH 8.5)
0, 10, 20, 50, 100, or 200mM β -NMN
( The purity of β -NMN in the assay sample was assumed to be 100%. In addition, beta-NMN was pre-dissolved in 100mM sodium carbonate solution )
Enzyme solution-
(I)R-LDH5
The enzyme solution was adjusted so that the final concentration of LDH in the reaction solution reached 245U/mL.
(II) human-derived LDH1
The enzyme solution was adjusted so that the final concentration of LDH in the reaction solution reached 45U/mL.
The results of the measurement showed that, when R-LDH5 was used, the enzyme activity of product 1 could not be measured at a concentration of 200mM of β -NMN, and the concentration dependence could not be followed (FIG. 4A). The reason is considered to be that: as the concentration of β -NMN becomes higher, the unexplained inhibition reaction increases. As the β -NMN concentration increases in product 2 (fig. 4B) and product 3 (fig. 4C), the difference in activity value with respect to the β -NMN compound of production example 1 increases.
In the case of using human-derived LDH1, the difference in activity value with respect to the β -NMN compound of production example 1 increased as the β -NMN concentration increased in each of product 1 (fig. 4D), product 2 (fig. 4E), and product 3 (fig. 4F).
(test example 5)
< Effect of NMN in cultured cells >
In order to evaluate the bioactivity of the β -NMN compound in production example 1 and β -NMN preparation 3, cultured cells were cultured in a medium containing the β -NMN compound, and the change in intracellular NAD was measured.
HEK293 cells treated by suspension (floating) were used as the cells for culture. FreeStyle was used as the culture medium TM 293 expression medium (manufactured by Saimer Feishel technologies).
First, the suspension treated HEK293 cells were allowed to reach 1X 10 in the culture medium 6 Each cell was prepared in a volume of 30mL in 6 125mL flasks. The beta-NMN compounds of preparation example 1 and beta-NMN preparation 3 were added to each flask so that the final concentrations thereof became 0 to 0.1mM, and CO was maintained at 37 ℃ without changing the medium 2 Culturing for 7 days in an incubator by shaking.
After shaking culture for 7 days, the cells and culture supernatant were recovered for various analyses. First, in order to calculate the cytotoxicity rate, the activity of aspartate Aminotransferase (AST) inside and outside the cell was measured using L-type Wako AST.J. 2 (manufactured by Fuji film and Wako pure chemical industries, ltd.) by a Hitachi autoanalyzer model 7180 (manufactured by Hitachi Seisakusho Co., ltd.) according to a method specified by the reagent to detect the ease enzyme. In addition, in order to measure the intracellular NAD content, NAD was detected using an NAD/NADH assay kit (manufactured by Dojindo laboratories Inc.). Specifically, the weight of the collected cells was measured, and after extraction with an extraction buffer attached to the kit, NAD was measured. The intracellular NAD content was calculated from a calibration curve obtained by measuring NAD solutions at respective concentrations.
Fig. 5A shows the cytotoxicity rates determined from the intracellular and extracellular AST activities when the β -NMN compound of production example 1 was used, and fig. 5B shows the cytotoxicity rates determined from the intracellular and extracellular AST activities when the β -NMN compound of β -NMN product 3 was used. Fig. 6A shows the intracellular NAD content when the β -NMN compound of production example 1 was used, and fig. 6B shows the intracellular NAD content when the β -NMN compound of β -NMN preparation 3 was used. The measurement results showed that the cell toxicity rate due to the lack of nutrients was lower than that of the case of adding the β -NMN product 3 when the β -NMN compound of production example 1 was added and cultured for 7 days without changing the medium, and that the intracellular NAD content was higher when the β -NMN compound of production example 1 was added than when the β -NMN compound of β -NMN product 3 was added.
Sequence listing
<110> Oriental Yeast Industrial Co Ltd
<120> Compound containing beta-nicotinamide mononucleotide or pharmacologically acceptable salt thereof, method for evaluating quality thereof, and method for determining enzymatic reactivity
<130> NOK00121P
<150> JP 2020-058429
<151> 2020-03-27
<160> 4
<170> PatentIn version 3.5
<210> 1
<211> 332
<212> PRT
<213> Rabbit
<400> 1
Met Ala Ala Leu Lys Asp Gln Leu Ile His Asn Leu Leu Lys Glu Glu
1 5 10 15
His Val Pro Gln Asn Lys Ile Thr Val Val Gly Val Gly Ala Val Gly
20 25 30
Met Ala Cys Ala Ile Ser Ile Leu Met Lys Asp Leu Ala Asp Glu Leu
35 40 45
Ala Leu Val Asp Val Met Glu Asp Lys Leu Lys Gly Glu Met Met Asp
50 55 60
Leu Gln His Gly Ser Leu Phe Leu Arg Thr Pro Lys Ile Val Ser Gly
65 70 75 80
Lys Asp Tyr Ser Val Thr Ala Asn Ser Lys Leu Val Ile Ile Thr Ala
85 90 95
Gly Ala Arg Gln Gln Glu Gly Glu Ser Arg Leu Asn Leu Val Gln Arg
100 105 110
Asn Val Asn Ile Phe Lys Phe Ile Ile Pro Asn Val Val Lys Tyr Ser
115 120 125
Pro His Cys Lys Leu Leu Val Val Ser Asn Pro Val Asp Ile Leu Thr
130 135 140
Tyr Val Ala Trp Lys Ile Ser Gly Phe Pro Lys Asn Arg Val Ile Gly
145 150 155 160
Ser Gly Cys Asn Leu Asp Ser Ala Arg Phe Arg Tyr Leu Met Gly Glu
165 170 175
Arg Leu Gly Val His Ala Leu Ser Cys His Gly Trp Ile Leu Gly Glu
180 185 190
His Gly Asp Ser Ser Val Pro Val Trp Ser Gly Met Asn Val Ala Gly
195 200 205
Val Ser Leu Lys Thr Leu His Pro Glu Leu Gly Thr Asp Ala Asp Lys
210 215 220
Glu Gln Trp Lys Gln Val His Lys Gln Val Val Asp Ser Ala Tyr Glu
225 230 235 240
Val Ile Lys Leu Lys Gly Tyr Thr Ser Trp Ala Ile Gly Leu Ser Val
245 250 255
Ala Asp Leu Ala Glu Ser Ile Met Lys Asn Leu Arg Arg Val His Pro
260 265 270
Ile Ser Thr Met Ile Lys Gly Leu Tyr Gly Ile Lys Glu Asp Val Phe
275 280 285
Leu Ser Val Pro Cys Val Leu Gly Gln Asn Gly Ile Ser Asp Val Val
290 295 300
Lys Val Thr Leu Thr Ser Glu Glu Glu Ala His Leu Lys Lys Ser Ala
305 310 315 320
Asp Thr Leu Trp Gly Ile Gln Lys Glu Leu Gln Phe
325 330
<210> 2
<211> 334
<212> PRT
<213> human
<400> 2
Met Ala Thr Leu Lys Glu Lys Leu Ile Ala Pro Val Ala Glu Glu Glu
1 5 10 15
Ala Thr Val Pro Asn Asn Lys Ile Thr Val Val Gly Val Gly Gln Val
20 25 30
Gly Met Ala Cys Ala Ile Ser Ile Leu Gly Lys Ser Leu Ala Asp Glu
35 40 45
Leu Ala Leu Val Asp Val Leu Glu Asp Lys Leu Lys Gly Glu Met Met
50 55 60
Asp Leu Gln His Gly Ser Leu Phe Leu Gln Thr Pro Lys Ile Val Ala
65 70 75 80
Asp Lys Asp Tyr Ser Val Thr Ala Asn Ser Lys Ile Val Val Val Thr
85 90 95
Ala Gly Val Arg Gln Gln Glu Gly Glu Ser Arg Leu Asn Leu Val Gln
100 105 110
Arg Asn Val Asn Val Phe Lys Phe Ile Ile Pro Gln Ile Val Lys Tyr
115 120 125
Ser Pro Asp Cys Ile Ile Ile Val Val Ser Asn Pro Val Asp Ile Leu
130 135 140
Thr Tyr Val Thr Trp Lys Leu Ser Gly Leu Pro Lys His Arg Val Ile
145 150 155 160
Gly Ser Gly Cys Asn Leu Asp Ser Ala Arg Phe Arg Tyr Leu Met Ala
165 170 175
Glu Lys Leu Gly Ile His Pro Ser Ser Cys His Gly Trp Ile Leu Gly
180 185 190
Glu His Gly Asp Ser Ser Val Ala Val Trp Ser Gly Val Asn Val Ala
195 200 205
Gly Val Ser Leu Gln Glu Leu Asn Pro Glu Met Gly Thr Asp Asn Asp
210 215 220
Ser Glu Asn Trp Lys Glu Val His Lys Met Val Val Glu Ser Ala Tyr
225 230 235 240
Glu Val Ile Lys Leu Lys Gly Tyr Thr Asn Trp Ala Ile Gly Leu Ser
245 250 255
Val Ala Asp Leu Ile Glu Ser Met Leu Lys Asn Leu Ser Arg Ile His
260 265 270
Pro Val Ser Thr Met Val Lys Gly Met Tyr Gly Ile Glu Asn Glu Val
275 280 285
Phe Leu Ser Leu Pro Cys Ile Leu Asn Ala Arg Gly Leu Thr Ser Val
290 295 300
Ile Asn Gln Lys Leu Lys Asp Asp Glu Val Ala Gln Leu Lys Lys Ser
305 310 315 320
Ala Asp Thr Leu Trp Asp Ile Gln Lys Asp Leu Lys Asp Leu
325 330
<210> 3
<211> 332
<212> PRT
<213> human
<400> 3
Met Ala Thr Leu Lys Asp Gln Leu Ile Tyr Asn Leu Leu Lys Glu Glu
1 5 10 15
Gln Thr Pro Gln Asn Lys Ile Thr Val Val Gly Val Gly Ala Val Gly
20 25 30
Met Ala Cys Ala Ile Ser Ile Leu Met Lys Asp Leu Ala Asp Glu Leu
35 40 45
Ala Leu Val Asp Val Ile Glu Asp Lys Leu Lys Gly Glu Met Met Asp
50 55 60
Leu Gln His Gly Ser Leu Phe Leu Arg Thr Pro Lys Ile Val Ser Gly
65 70 75 80
Lys Asp Tyr Asn Val Thr Ala Asn Ser Lys Leu Val Ile Ile Thr Ala
85 90 95
Gly Ala Arg Gln Gln Glu Gly Glu Ser Arg Leu Asn Leu Val Gln Arg
100 105 110
Asn Val Asn Ile Phe Lys Phe Ile Ile Pro Asn Val Val Lys Tyr Ser
115 120 125
Pro Asn Cys Lys Leu Leu Ile Val Ser Asn Pro Val Asp Ile Leu Thr
130 135 140
Tyr Val Ala Trp Lys Ile Ser Gly Phe Pro Lys Asn Arg Val Ile Gly
145 150 155 160
Ser Gly Cys Asn Leu Asp Ser Ala Arg Phe Arg Tyr Leu Met Gly Glu
165 170 175
Arg Leu Gly Val His Pro Leu Ser Cys His Gly Trp Val Leu Gly Glu
180 185 190
His Gly Asp Ser Ser Val Pro Val Trp Ser Gly Met Asn Val Ala Gly
195 200 205
Val Ser Leu Lys Thr Leu His Pro Asp Leu Gly Thr Asp Lys Asp Lys
210 215 220
Glu Gln Trp Lys Glu Val His Lys Gln Val Val Glu Ser Ala Tyr Glu
225 230 235 240
Val Ile Lys Leu Lys Gly Tyr Thr Ser Trp Ala Ile Gly Leu Ser Val
245 250 255
Ala Asp Leu Ala Glu Ser Ile Met Lys Asn Leu Arg Arg Val His Pro
260 265 270
Val Ser Thr Met Ile Lys Gly Leu Tyr Gly Ile Lys Asp Asp Val Phe
275 280 285
Leu Ser Val Pro Cys Ile Leu Gly Gln Asn Gly Ile Ser Asp Leu Val
290 295 300
Lys Val Thr Leu Thr Ser Glu Glu Glu Ala Arg Leu Lys Lys Ser Ala
305 310 315 320
Asp Thr Leu Trp Gly Ile Gln Lys Glu Leu Gln Phe
325 330
<210> 4
<211> 334
<212> PRT
<213> pig
<400> 4
Met Ala Thr Leu Lys Glu Lys Leu Ile Ala Pro Val Ala Glu Glu Glu
1 5 10 15
Thr Thr Ile Pro Asn Asn Lys Ile Thr Val Val Gly Val Gly Gln Val
20 25 30
Gly Met Ala Cys Ala Ile Ser Ile Leu Gly Lys Ser Leu Thr Asp Glu
35 40 45
Leu Ala Leu Val Asp Val Leu Glu Asp Lys Leu Lys Gly Glu Met Met
50 55 60
Asp Leu Gln His Gly Ser Leu Phe Leu Gln Thr Pro Lys Ile Val Ala
65 70 75 80
Asp Lys Asp Tyr Ser Val Thr Ala Asn Ser Lys Ile Val Val Val Thr
85 90 95
Ala Gly Val Arg Gln Gln Glu Gly Glu Ser Arg Leu Asn Leu Val Gln
100 105 110
Arg Asn Val Asn Val Phe Lys Phe Ile Ile Pro Gln Ile Val Lys Tyr
115 120 125
Ser Pro Asp Cys Ile Ile Ile Val Val Ser Asn Pro Val Asp Ile Leu
130 135 140
Thr Tyr Val Thr Trp Lys Leu Ser Gly Leu Pro Lys His Arg Val Ile
145 150 155 160
Gly Ser Gly Cys Asn Leu Asp Ser Ala Arg Phe Arg Tyr Leu Met Ala
165 170 175
Glu Lys Leu Gly Val His Pro Ser Ser Cys His Gly Trp Ile Leu Gly
180 185 190
Glu His Gly Asp Ser Ser Val Ala Val Trp Ser Gly Val Asn Val Ala
195 200 205
Gly Val Ser Leu Gln Glu Leu Asn Pro Glu Met Gly Thr Asp Asn Asp
210 215 220
Ser Glu Asn Trp Lys Glu Val His Lys Met Val Val Glu Ser Ala Tyr
225 230 235 240
Glu Val Ile Lys Leu Lys Gly Tyr Thr Asn Trp Ala Ile Gly Leu Ser
245 250 255
Val Ala Asp Leu Ile Glu Ser Met Leu Lys Asn Leu Ser Arg Ile His
260 265 270
Pro Val Ser Thr Met Val Gln Gly Met Tyr Gly Ile Glu Asn Glu Val
275 280 285
Phe Leu Ser Leu Pro Cys Val Leu Asn Ala Arg Gly Leu Thr Ser Val
290 295 300
Ile Asn Gln Lys Leu Lys Asp Asp Glu Val Ala Gln Leu Lys Asn Ser
305 310 315 320
Ala Asp Thr Leu Trp Gly Ile Gln Lys Asp Leu Lys Asp Leu
325 330
Claims (8)
1. A compound which is a compound comprising β -nicotinamide mononucleotide or a pharmacologically acceptable salt thereof, characterized in that: the purity by HPLC measurement is 95% or more, and the reactivity to lactate dehydrogenase is 30 units or more.
2. The compound according to claim 1, which has a purity of 98% or more as measured by HPLC and a reactivity to lactate dehydrogenase of 33 units or more.
3. The compound of claim 1 or 2 in crystalline form.
4. The compound of any one of claims 1 to 3, wherein lactate dehydrogenase is a lactate dehydrogenase derived from skeletal muscle of a mammal.
5. The compound of claim 4, wherein the lactate dehydrogenase has the amino acid sequence of SEQ ID NO 1.
6. The compound of any one of claims 1 to 5, which is substantially free of nicotinamide dinucleotide.
7. A method for evaluating the quality of a compound containing β -nicotinamide mononucleotide or a pharmacologically acceptable salt thereof, comprising:
the quality of the compound containing beta-nicotinamide mononucleotide or a pharmacologically acceptable salt thereof is evaluated using as an index a purity of 95% or more as measured by HPLC and a reactivity to lactate dehydrogenase of 30 units or more.
8. A method for determining enzymatic reactivity of a compound containing β -nicotinamide mononucleotide or a pharmacologically acceptable salt thereof, comprising:
the reactivity of the compound containing beta-nicotinamide mononucleotide or a pharmacologically acceptable salt thereof with respect to lactate dehydrogenase is determined using as an index a purity of 95% or more as measured by HPLC and a reactivity with respect to lactate dehydrogenase of 30 units or more.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2020058429 | 2020-03-27 | ||
| JP2020-058429 | 2020-03-27 | ||
| PCT/JP2021/004912 WO2021192683A1 (en) | 2020-03-27 | 2021-02-10 | COMPOUND COMPRISING β-NICOTINAMIDE MONONUCLEOTIDE OR PHARMACOLOGICALLY ACCEPTABLE SALT THEREOF, AND METHOD FOR EVALUATING QUALITY AND METHOD FOR ASSESSING ENZYMATIC REACTIVITY OF SAID COMPOUND |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115427422A true CN115427422A (en) | 2022-12-02 |
Family
ID=77891415
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202180024394.2A Pending CN115427422A (en) | 2020-03-27 | 2021-02-10 | Compound comprising beta-nicotinamide mononucleotide or pharmacologically acceptable salt thereof, method for evaluating quality thereof, and method for determining enzymatic reactivity |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US20230348520A1 (en) |
| JP (1) | JPWO2021192683A1 (en) |
| CN (1) | CN115427422A (en) |
| WO (1) | WO2021192683A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN118591635A (en) * | 2022-01-28 | 2024-09-03 | 东方酵母工业株式会社 | Method for stabilizing nicotinamide adenine dinucleotide and composition for stabilizing |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104817604B (en) * | 2015-03-16 | 2017-08-04 | 邦泰生物工程(深圳)有限公司 | A kind of purification process of β nicotinamide mononucleotides |
| GB2542881B (en) * | 2015-10-02 | 2020-01-01 | Carr Andrew | Crystal forms of ß-nicotinamide mononucleotide |
| US10174298B2 (en) * | 2016-07-30 | 2019-01-08 | Bontac Bio-Engineering(Shenzhen) Co., Ltd | Nicotinamide phosphoribosyltransferase (NAMPT) mutant and use thereof |
| WO2018047715A1 (en) * | 2016-09-06 | 2018-03-15 | 協和発酵バイオ株式会社 | CRYSTALS OF β-NICOTINAMIDE MONONUCLEOTIDE AND PRODUCTION PROCESS THEREFOR |
-
2021
- 2021-02-10 JP JP2022509376A patent/JPWO2021192683A1/ja active Pending
- 2021-02-10 CN CN202180024394.2A patent/CN115427422A/en active Pending
- 2021-02-10 WO PCT/JP2021/004912 patent/WO2021192683A1/en active Application Filing
- 2021-02-10 US US17/907,346 patent/US20230348520A1/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| US20230348520A1 (en) | 2023-11-02 |
| JPWO2021192683A1 (en) | 2021-09-30 |
| WO2021192683A1 (en) | 2021-09-30 |
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